The present invention relates to polymeric derivatives of camptothecin and related topoisomerase inhibitor compounds. More particularly, the invention relates to camptothecin derivatives in which the E ring lactone has been modified to allow attachment of substantially non-antigenic polymers.
Camptothecin is a water-insoluble cytotoxic alkaloid produced by Camptotheca accuminiata trees indigenous to China and Nothapodytes foetida trees indigenous to India. Camptothecin and related analogs are known to be potential anticancer agents and have demonstrated therapeutic activity in vitro and in vivo.
Over the years, various proposals have been made to increase the water solubility and/or therapeutic and pharmacokinetic properties of camptothecin analogs. One early attempt to increase the water solubility of camptothecin is disclosed in U.S. Pat. No. 4,943,579 (hereinafter the ""579 patent). The ""579 patent discloses certain simple 20(S)-camptothecin amino acid esters in their salt forms as water soluble prodrugs. As evidenced by the data provided in Table 2 of the ""579 patent, hydrolysis is rapid. Consequently, at physiologic pH, the insoluble base is rapidly generated after injection, binds to proteins and is quickly eliminated from the body before full therapeutic effect can be achieved. A related effort was directed to developing a water-soluble camptothecin sodium salt. Unfortunately, the water-soluble sodium salt of camptothecin remained too toxic for clinical application (Gottlieb et al,. 1970 Cancer Chemotlier, Rep. 54, 461; Moertel et al,. 1972 ibid, 56, 95; Gottlieb et al., 1972 ibid, 56, 103).
Other attempts at improving the solubility of camptothecin analogs are provided by Greenwald et al. For example, commonly-assigned U.S. Pat. No. 5,965,566 discloses camptothecin attached to a bifunctional PEG using an amino acid-based linkers. U.S. Pat. No. 6,011,042 discloses polymeric derivatives of 10-hydroxycamptothecin. The PEG-derivatives provide the artisan with a water soluble prodrug which, upon administration, eventually liberate the parent compound in vivo. Prodrugs allow the artisan to modify the onset and/or duration of action of an agent in vivo and can modify the transportation, distribution or solubility of a drug in the body. Furthermore, prodrug formulations often reduce the toxicity and/or otherwise overcome difficulties encountered when administering pharmaceutical preparations.
The E-lactone ring is thought to be essential for anti-cancer activity. Nonetheless, Sawada et al. have suggested in U.S. Pat. No. 4,914,205 and Chem. Pharm. Bull. 41(2) 310-313 (1993) prodrugs of camptothecin and the 7-ethyl derivative thereof having a modified E-lactone-ring. Specifically, the E-lactone ring is opened to provide 17-O-acyl derivatives and the authors demonstrated improved solubility of HCl salts thereof when compared to the native alkaloid. In spite of the increases in solubility demonstrated by the open lactone E-ring derivatives, further improvements have been sought. For example, after administration, the prodrug must be converted back into its active form in order to have biological (anticancer) activity. Consequently, these derivatives are highly dependent upon the hydrolysis of the respective hydroxy-acids to free the 17-hydroxyl group in order to regenerate the E-ring lactone. Such conversions, however, are difficult to predict. It would be highly desirable to provide E-lactone ring modified camptothecin analogs with extended circulating half lives and more predictable rates of regenerating the closed lactone ring. The present invention addresses this need.
In one aspect of the invention, compounds of Formula (I) are provided: 
wherein:
R1 is selected from the group consisting of amino acid residues, peptide residues containing from about 2 to about 10 amino acids, Y3xe2x80x94(L2)pxe2x80x94A2 and R2;
Y3 is O, S or NR3;
p is zero or one;
L2 is a bifunctional linker;
Y1 s O, S, or NR4;
Y2 is O, S, CR5R6 or NR7;
L1 is a bifunctional linker;
a and b are independently zero or one;
A1 and A2 are independently selected from the group consisting of hydrogen, amino protecting groups, NR8R9, amino acid residues, peptide residues containing from about 2 to about 10 amino acids; polymeric residues, R10, SR11, NC(O)R12;
D3-D7 are independently selected from the group consisting of H, C1-8 straight or branched alkyls, substituted C1-8 straight or branched alkyls, aryls, substituted aryls, arylalkyls, substituted aryalkyls, C1-8 allkylaryls, C1-8 alkoxys, C1-8 hydroxy-alkyls, C1-8 aminoalkoxy, aryloxys, gycals, CO3R13, R14, nitro, cyano, halo, hydroxyl, amino, SR15, NR16R17 or OR18, where D4 and D5 optionally, when taken together, form a saturated 3-7 membered heterocyclic ring which may contain O, S or NR19 groups, where R19 is hydrogen or a C1-6 alkyl;
D8-D9 are independently selected from the group consisting of H, C1-8 straight or branched alkyls, substituted C1-8 straight or branched alkyls, aryls, substituted aryls, arylalkyls, substituted aryalkyls, C1-8 allkylaryls and C1-8 hydroxy alkyls; and
R2-18 are independently selected from the group consisting of hydrogen, C1-6 alkyls, C3-19 branched alkyls, C3-8 cycloalkyls, C1-6 substituted alkyls, C3-8 substituted cycloalkyls, aryls, substituted aryls, aralkyls, C1-6 heteroalkyls, substituted C1-6 heteroalkyls, C1-6 alkoxy, phenoxy and C1-6 heteroalkoxy; except that at least one of A1 and A2 comprise a polymeric residue.
In another aspect of the invention there is provided bifunctional compounds that are formed when at least one of A1 and A2 comprises a polymeric residue and the polymeric residue is functionalized on both the alpha and omega termini to allow two equivalents of the camptothecin to be delivered per equivalent of the polymer which is preferably PEG. Such preferred compositions correspond to formulae (IIIa) and IIIb) below: 
wherein all variables are as previously defined above.
For purposes of the present invention, the term xe2x80x9cresiduexe2x80x9d shall be understood to mean that portion of a camptothecin derivative or bifunctional spacer which remains after it has undergone a substitution reaction.
Methods of preparing the compositions of the invention and methods of treatment using the same are also provided.
For purposes of the present invention, the term xe2x80x9cpolymeric residuexe2x80x9d or xe2x80x9cPEG residuexe2x80x9d shall each be understood to mean that portion of the polymer or PEG which remains after it has undergone a reaction with a heteroaromatic amine-containing compound.
For purposes of the present invention, the term xe2x80x9calkylxe2x80x9d shall be understood to include straight, branched, substituted, e.g. halo-, alkoxy-, nitro-, C1-12 alkyls, C3-8 cycloalkyls or substituted cycloalkyls, etc.
For purposes of the present invention, the term xe2x80x9csubstitutedxe2x80x9d shall be understood to include adding or replacing one or more atoms contained within a functional group or compound with one or more different atoms.
For purposes of the present invention, substituted alkyls include carboxyalkyls, aminoalkyls, dialkylaminos, hydroxyalkyls and mercaptoalkyls; substituted alkenyls include carboxyalkenyls, aminoalkenyls, dialkenylaminos, hydroxyalkenyls and mercaptoalkenyls; substituted alkynyls include carboxyalkynyls, aminoalkynyls, dialkynylaminos, hydroxyalkynyls and mercaptoalkynyls; substituted cycloalkyls include moieties such as 4-chlorocyclohexyl; aryls include moieties such as napthyl; substituted aryls include moieties such as 3-bromo-phenyl; aralkyls include moieties such as toluyl; heteroalkyls include moieties such as ethylthiophene; substituted heteroalkyls include moieties such as 3-methoxy-thiophene; alkoxy includes moieties such as methoxy; and phenoxy includes moieties such as 3-nitrophenoxy. Halo- shall be understood to include fluoro, chloro, iodo and bromo.
The term xe2x80x9csufficient amountsxe2x80x9d for purposes of the present invention shall mean an amount which achieves a therapeutic effect as such effect is understood by those of ordinary skill in the art.
One advantage of the invention is that the artisan is provided with prodrugs of camptothecin derivatives with improved aqueous solubility.
Another advantage of the compounds of the invention is that in certain preferred embodiments, the releasble polymer not only extends the circulating life of the camptothecin derivative, but it also provides a means for controlling conversion of the open E-ring lactone back to the biologically active form. This result is achieved by virtue of the fact that the open E-ring camptothecin derivative cannot hydrolyze into the closed E lactone ring until the polymer is released.